Gastrointestinal Stromal Tumor (GIST) is the most common sarcoma in the U.S. Sporadic GIST is often caused by somatic mutations in KIT, PDGFR?, or BRAF genes, while hereditary GIST syndromes are caused by germline KIT, NF-1, or succinate dehydrogenase (SDH) mutations. Our epidemiologic data under peer review suggests that 17.1% of sporadic GIST patients develop ?1 additional malignancies not associated with familial GIST syndromes, including Non-Hodgkin's lymphoma, carcinoid tumors, and melanoma, as well as colorectal, esophageal, pancreatic, hepatobiliary, non-small cell lung, prostate, and renal cell cancers. This raises the question as to whether a subset of sporadic GIST patients have an unacknowledged multi-tumor syndrome(s) caused by yet to be determined heritable genomic alteration(s). We hypothesize the existence of GIST multiple tumor syndrome(s) (GMTS) with distinct tumor phenotype(s) from those previously identified in known familial GIST syndromes that result from the inheritance of one or more deleterious germline mutation(s). Our overall objective is to determine the heritable genomic cause(s) that may lead to the concomitant development of GIST and additional malignancies that we have identified as having higher incidences/prevalence within the GIST patient population. In Aim 1, we will sequence the germline whole exome of 50 unrelated individuals with sporadic GIST and one or more additional malignancies. We will select: 1) ?10 patients with at least two additional malignancies; 2) 10 patients that are 40-50 years of age with one or more additional malignancies; and 3) patients with a strong family history of cancer with one or more additional malignancies. Next generation sequencing and variant selection will be performed in order to characterize the genomic germline landscape of these patients. We will then perform Sanger sequencing in order to validate any critical/pathogenic mutations identified by whole exome sequencing. Once we have identified a set of critical mutations/genes/pathways, we will perform focused, independent Sanger sequencing in the germline DNA of a cohort of sporadic GIST patients without GMTS (N=50) in order to validate our findings as unique to GMTS patients. In Aim 2, we will sequence these patients' respective GIST for somatic KIT, PDGFR?, and BRAF mutations in order to determine if one or more somatic mutations are unique in this patient population or correlate with germline genomic findings, and therefore may serve as a potential somatic biomarker of GMTS in sporadic GIST patients. Concomitant with these analyses, we will analyze the demographics and tumor-specific details for each patient studied. If germline mutations are identified as putative disease drivers, our proposal has the potential for rapid translational application to the clinic as the characterization of novel hereditary cancer syndrome(s) would have implications for: 1) altered cancer screening recommendations; 2) prevention strategies; 3) familial genetic counseling and screening; and 4) developing anti-cancer therapies against unappreciated targets in these diseases.